Adoptive cell therapy (ACT) using ex vivo differentiated type-I CD8+ cytotoxic T (Tc1) cells has shown significant clinical promise for the treatment of established cancers. Recent clinical trials using ACT combined with lymphodepletion have resulted in objective responses in 50-70% of patients with advanced melanoma. However, complete responses remain infrequent with most patients, and improvements to this approach are needed. Current understanding of determinants of successful CD8+ T-cell adoptive therapy includes, but is not limited to, persistence of transferred T cells, differentiation status of transferred T cells, telomere length, and lymphodepleting condition. In particular, administration of naïve or early effector T cells in combination with active immunization and IL-2 can result in eradication of large established tumors.
Cytokine priming signals direct CD8+ T cells to acquire unique profiles that affect their ability to mediate specific immune responses. CD8+ T cells can acquire cytokine secreting phenotypes that require transcription factors similar to those of T helper (Th) cells. Tc1 cells secrete IFN-γ and kill tumor targets by releasing cytotoxic molecules such as GrzB and Perforin. The contribution of adoptively transferred Tc1 cells in antitumor responses has been clearly established, and Tc1 has stronger therapeutic effect than Tc2 and regulatory CD8+ T cells. In addition, naïve CD8+ T cells can be differentiated into Tc17 cells in Th17 polarizing conditions. IL-17 and IL-17-producing T cells are tumor-promoting factors and can mediate IL-6-induced Stat3 activation to generate protumorigenic environment, which may limit the application of Tc17 for adoptive therapy.
IL-9 is a pleiotropic cytokine that has direct and indirect effects on multiple cell types. It has recently been reported that Th9 cell-derived IL-9 not only inhibited tumor progression, but also promoted greater tumor clearance than Th1 cells that have traditionally been considered as the most efficient CD4+ T-cell subset to generate antitumor immunity. Nevertheless, identification of CD8+ T-cell subsets with optimal therapeutic potential remains a critical challenge for the advances of cancer immunotherapy.